16-formyl-16-androstenes



United States Patent Ofifice Patented Mar. 5, 1963 3,080,389 lfi-FORNEYL-l-ANDRQSTENES Albert Bowers and Percy George Bolton, Mexico City, Mexico, assignors to Syntex Corporation, a corporation of Panama No Drawing. Filed Aug. 31, 1961, Ser. No. 135,156 21 Claims. (Cl. 260--397.3)

U I y In the above formulas, R represents "hydrogen or methyl; R represents fluorine, chlorine or methyl and R represents hydrogen or methyl. 'R 'and R may also be lower alkyl.

The compounds represented by the above formulas are anti-androgenic agents. Further, they exhibit anti-estrogenic and anti-gonadotrophic activities and lower the blood cholesterol level. They also are appetite stimulants and anti-progestational agents.

The novel compounds of the present invention are prepared by the process illustrated by the following equation:

R a =OHOMe :OHOMe ..1 Q IQ i f O 0 [O I V VI R3 R:

l Alfi cflo l \-OHO L/QI R O- VIII a O: VII

in {a In the above formulas, R and R have the same meaning as heretofore set forth; R may be hydrogen, fluorine, chlorine or methyl. When R is methyl, R is hydrogen and when R is fluorine, chlorine or methyl, R is hydrogen.

In practicing the process outlined above, the starting testosterone derivative (1) or the corresponding 19-nor compound is treated with ethylene glycol in an acid mediumthus affording the corresponding 3-cycloethylenedi oxy-Afi-androstene derivative (ll). Oxidation of the 17,B-

hydroxyl group preferably with chromium trioxidepyridine, furnishes the 17-ketone (III) which upon treatment with ethyl formate in the presence of an alkali metal hydride, such as sodium hydride, and subsequent reaction of the formed metal salt in an acid medium, affords the corresponding 16-hydroxymethylene-3 cycloethylenedioxy-A -androstene-17-one derivative (IV).

Methylation of the 16-hydroxymethylene group with a suitable agent such as diazomethane, furnishes the corresponding l-methoxymethylene derivative (V). Reduction of the 17-keto group of this compound, preferably with sodium borohydride, affords the corresponding 17B- hydroxy-16-rnethoxymethylene-3-cyclocthylenedioxy A androstene derivative (VI) which upon treatment in a mild acid medium furnishes the respective l6-formyl- A -androstadien-3-one compound (VII) or the corresponding l9-nor derivative.

The l6-formyl-A -androstadiene compounds containing the methyl group at C1() (VII; R=CH upon treatment with a suitable dehydrogenating agent such as 2,3-dichloro-5,6-dicyano-1,4 benzoquinone, aiiords the corresponding l6-formyl-A -androstatriene compounds (VIII).

The following specific examples serve to illustrate, but are not intended to limit the scope of the present invention:

Example I A mixture of 5 g. of testosterone, cc. of anhydrous benzene, 60 cc. of ethylene glycol distilled over sodium hydroxide and 800 mg. of p-toluenesulfonic acid monohydrate was refluxed for 12 hours with the use of an adapter for the continuous removal of the water formed during the reaction. Aqueous sodium bicarbonate solution was added to the cooled mixture and the organic phase was separated, washed with Water, dried over ana a hydrous sodium sulfate and evaporated to dryness. The residue crystallized from acetone-hexane to give 3-cycloethylenedioxy-A -androsten-l7fi-ol.

Following the same technique, there were treated the starting compounds hereinafter listed, thus aiiording the corresponding products set forth below.

Starting compounds Products IQ-nor-testosterone 3-cyc1oethylenedioxy-lg-nor-mandrosten-17B-o1. 2a-methyl-testosterone j 2mmethyl-3-cycloethyleriedioxy- A -androsten-17B-0l. 2a-methyI-H-cycloethylenedioxy- 19-nor-A -androsten-l7fi-ol. Ga-fluor-3-cycloethylenedi0xy- N-androsten-l'Z/S-ol. fiu-fluoro-3-cycloethylenedioxy- 19-nor-A -androsten-17Bol. 6a-chloro-3-cycloethylenedioxy- A -androsten-lw-ol. 6a-chlor0-3cyc1oethylenedioxy- 19-110r-N-androstemflfl-ol. 6Q-methyHeypIoethylenedioxy- A -androsten-17B-o1. Ga-methyl-S-eycloethylenedioxy- IQ-nor-N-androstsn-17B-ol.

2mmethyl-IS-nor-testosterone fia-fluoro-testosterone 6a-fluoro-19-nor-testosterone 6a-ehloro-testosterone 6a-chloro-19-nor-testosterone fia-methyl-testosterdne 6a-methyl-lQ-nor-testosterone Example 11 A solution of 4 g. of 3-cycloethylenedioxy-A androsten-l7fi-ol in 80cc. of pyridine was added to a mixture of 4 g. of chromic trioxide in 80 cc. of pyridine. The reaction mixture was kept at room temperature overnight. It was then diluted with ethyl acetate, filtered through celite and the filtrate washed well with water, dried and evaporated to dryness. Crystallization from acetonehexane afiorded 3-cycloethylenedioxy-A -androsten-l7- one.

By the same procedure there were oxidized the starting compounds set forth below, thus furnishing the corresponding products hereinafter listed:

Starting compounds Products 3-cycloethylenedioxy-19-nor-A androsten-17-one.

2a-methyl-3-cycloethylenedioxy- A -andr0sten-17-0ne.

2a-methyl-3-cycloethylenedioxylQ-nor-N-androsten-17-one.

6a-fiuoro-3-eycloethylenedioxy-N- androSten-N-one.

' 6a-chloro-3-eycloethylencdioxy-A androsten-l7-one.

Gar-ehloro-3 cycloethylendioxy-l9- nor-A -androsten-17-one.

6vi-methyl-Zl-cycloethylenedioxy- A androsten-Hhne.

Ga-methyI-Zi-eycloethylenedioxy- 19-nor-A androsten-17-one.

1G-hydroxymethylene-3- cycloethylenedioxy-lQ-nor-N- androsten-17-one.

16-11ydroxymethylene-2a-methyl- 3-cycloethylenedioxy-A androsten-17-one.

16-hydroXymethyIene-ZwmethyI- B-cycloethylenedioxy-lQ-nor-M- androsten-17-one.

16-11ydroxymethylene-Ga-fluqro- B-cycloethylenedioxy-M- androsten-l7-one.

' androsten-U-one.

16-hydroxymethylene'fia-eliloro- 3-cyeloethylenedioxy-A androsten-17-one. lfi-hydroxymethylene-fia-chloro- 3-cycloethylenedioxy-lQ-nor-A androsten-l'I-one. 16-hydroxy1nethylene-Ga-methyl- S-eycloethylenedioxy-M- androsten-17-one. 1fi-hydroxymethylene-fia-methyl- 3-cycloethylenedioxy-l -nor-A -'androsten-17-one.

Example IV set forth below:

- Starting compounds Products Starting compounds 3-cycloethylenedioxy-lQ-nor-M- -androsten-17B-ol. 2a-methyl-3-oycloethylenedioxy- A -androstend'ifi-ol. I 2a-methyl-3-cycloethylenedioxy- 19-nor-A ,androsten-175-ol. 6a-fluoro-3-oycloethylenedioxy-M- androstcn-Ufl-ol. 6a-fluoro-3-cyc1oethylenedioxy-19- nor-A -androsten-fl-one. 6a-ehlor0-3-cycloethy1enedioxy-A androsten-WB-ol. fia-chlor0-3-cycloethylenedioxy-19- nor-A -androsten-lm-ol. fiwmethyl-B-cyeloethylenedioxy- A -androsten-flflol Products 3-cycloethylenedioxy-lg nor-A androsten-17-one. 2a-methyl-3-cycloethylenedioxy- A -androsten-17-one. Za-methyl-3-cycloethylenedioxy- 1Q-nor-A -androsten-17-onc. 6a-fluoro-3-cycloethylenedioxy- M-androsten-l'l-one. 6a-fiuoro-3-cycloethylenedioxy-lQ- nor-N-androsten-H-one. 6a-chl0r0-3-eyeloethylencdioxy-n androsten-17-one. 6a-chloro-3-cycloethylenedioxy-l9- nor-A androsten-17-0ne. 6a-methyI-S-cycloethylenedioxy- A -androsten-17-one. fia-methyl-ii-eycloethylenedioxy- 19-nor-A -androsten-l7-one.

Example 111 I To a solution of 3 g. of 3-cycloethylenedioxy-A -androsten-17-one in 80 cc. of anhydrous benzene was added 3 cc. of ethyl formate and 1.3 g. of sodium hydride, suspended in mineral oil while cooling and stirring under an atmosphere of nitrogen. The mixture was stirred for 24 hours at room temperature, hexane was added until complete precipitation, the solid was collected and dried under vacuum. The crude material was suspended in aqueous tartaric acid and stirred at room temperature forhalf an hour. The precipitate was collected, washed with water and dried. Recrystallization from methylene chloridehexane gave 16-hydroxymethylene-3-cycloethylenedioxy- A -androsten-l7-one.

The startingcompounds listed below were'treated following the above described procedure furnishing" the corresponding products hereafterset forth.

1fi-hydroxymethylene-3-cycloethylenedioxy-lQ-nor-M- androsten-17-one. 16-hydroxymethylene-2a-methyl- 3-eycIoethy1enedioxy-A androsten-17-one. 1fi-hydroxymethylene-2a-rnethyl- 3-cycloetyhlenedioxy-lQ-nor-N- androsten-17-one. 16hydroxymethylene-(ia-fluorodcycloethylenedioxy-M- androsten-lWone. 16-11ydroxymethylene-Ga-fluoro- 3-cycloethylenedioxy-lQ-nor-N- androsten-17-one. lfi-hydroxymethylene-fia-chloro- 3-cycloethylenedioxy-A androsten-17-one. lfi-hydroxymethylene-fia-chloro- I 3-cycloethylenedioxy-lQ-nor-A androsten-17-o'ne. 16-hydroxyinethylenefiwmethyb S-cycloethylenedioxy-N- androsten-l7-one. lfi-hydroxymethylene-Ga-methyl- 3-cycloethylenedioxy-19-nor-A andr0sten-17-one.

16-methoxymethylene-Ii-cyeloethylenedioxy-lQ-nor-N- androsten-17-one. l6-rnethoxymethylene-2a-methyl- 3 cyc1oethylenedi0xy-A androsten-17-0ne. l6-methoxymethylene-Za-methyl- 3-eycloethylenedioxy-lQ-rior-N- androsten-17-0ne. 16-methoxymethylene-da-fiuoro- 3-cycloethylenedioxy-A androsten-17-o'ne. lfi-methoxyrnethylene-6crfluo1'o- 3-cyc1oethylenedi0xy-19-nor-A androsten-17-one. lfi-methoxymethylene-fia-ehloro- 3-cyeloe'thylenedioxy-A androsten-17-one. 16-methoxymethylene-fia-chloro- 3-cyc1oethylenedioxy-lQ-nor-A androsten-17-one. lfi-methoxymethylenefitemethyl- Beycloethylenedioxy-N- 'andr0sten-17-0ne. 16-methoxymethylene-Ga-methyl- 3-eycloethylenedioxy-w-nor-A andr0sten'17-one.

Example V trom acetone-hexane to give 16-methoxymethylene-3- 3-cycloethylenedioxy-A -androsten-l7 3-01.

Following the same procedure, there were treated the starting compounds listed below, affording the corresponding products hereinafter set forth:

Starting compounds Products 16-methoxymethylene-S-cycloethylenedioxy-lQ-nor-Mandrosten-17-one. 1G-methoxymethylene-h-methyl- 3-cycloethy1enedioxy-A androsten-17-one. 16-methoxymethylene-h-methyl- 3-cycloethylenedioxy-lQ-nor-N- androsten-17-one. lfi-methoxymethylenefia-fiuoro- 3-cycloethylenedioxy-A androsten-l7-one. Iii-methoxymethylene-6a-flu0ro- 3-cycloethylenedioxy-ltl-nor-A androsten-17-one. lfi-methoxymethylene-Ga-chloro- 3-cycloethylenedioxy-A andrsten-17-one. 1fi-methoxyrnethylene-fia-chloro- 3-cycloethylenedioxy-lQ-nor-M- androsten-17-one. 16-methoxymethylene-6a-methy1- 3-cycloethylenedioXy-A androsten-17-one. lfi-methoxymethylene-Ga-methy 3-cycloethylenedioXy-lQ-nor-N- androsten-None.

lfi-methoxymethylene-3-cycloethylenedioxy-lQ-nor-M-androsten-17B-ol. 16-methoxymethylene-2a-methyl- 3-cyc1oethylenedioxy-A androsten-17B-ol. 1G-methoxymethylene-h-methyl- 3-cycloethylenedioxy-lQ-nor-M- androsten-17B-ol. IG-methoxymethylene-Gu-fluoro- 3-cyc1oethylenedioXy-A androsten-17601. lfi-methoxymethylene-Ga-fiuoro- 3-cycloethylenedioxy-lQ-nor-M- androsten-1764)]. lfi-methoxymetliylene-fia-ehloro- 3-cycl0ethylenedioxyA androsten-171301. 16-methoxymethylene-fia-chloro- B-cycloethylenedioxy-lQ-nor-N- androsten-176ml. lfi-methoxyrnethylene-(Sa-methyl- B-oycloethylenedioxy-N- androsten-17fl-ol. lfi-methoxymethylene-fia-methyl- 3-cycloethylenedioxy-lQ-nor-M- androsten-17501.

Example VI A solution of 500 mg. of

16-rnethoxymethylene-3-cycloethylenedioxy-A -androsten-175-01 in 25 cc. of acetone was treated with 0.1 cc. of concentrated hydrochloric acid and the mixture was kept at room temperature overnight. It was then poured into water, extracted with methylene chloride, and the organic extract washed with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 16-forrnyl-A -androstadien-3-one.

The starting compounds listed below were treated by the same procedure affording hereinafter disclosed:

the corresponding products Starting compounds Products 16-methoxymethylene-IS-cycloethylenedioxy-lQ-nor-N- androsten-17,601. lfi-methoxymethylene'2a-methyl- 3-cycloethylenedioxy-A androsten-178m. 16-methoxymethylene-2a-methyl- 3-cycloethylenedioxy-19-nor-A andr0stenl7fl-ol. 16-methoxymethylene-fiwfluoro- 3-cyc1oethylenedioxy-A androsten-175m. 1G-methoxyrnethylene-fiu-fiuoro- 3-cycloethylenedioxy-lQ-nor-M- androsten-175ml. lfi-methoxymethylene-Ga-chloro- 3-cyoloethylenedioxy-A androsten-17501. lfi-methoxymethylene-Ga-chloro- S-cycloethylenedioxy-lQ-nor-A androsten-17B-ol. lfi-rnethoxymethylene-6a-methy1- 3-cyeloethylenedioxy-A androsten-17801. lfi-methoxyrnethylene-Ga-methyl- 3-cycloethylenedioxy-lQ-nor-M- androsten-17601.

16-formyl-2a-methyl-A androstadien-3-one.

l6-formy1-2a-methyl-19-nor- A -androstadien-3-0ne.

16-formyl-6a-chloro-A androstadien-3-one.

ISJOrmyI-Sa-methyI-A androstadien-3-0ne.

16-formyl-6a-methyld9-nor- A -androstadien3-one.

Example VII A mixture of 500 mg. of 16-formyl-A -androstadienrespectively obtained l6-formyl-2u-methyl-A -andrm statrien-3-one, 16 formyl-6ot-fiuoro-A -andr0stratrien- 3-one, 16 formyl 6oz chloro-A -androstatrien-3-0ne, and 16-formyl-6a-methyl-A -androstatrien-3-one.

We claim:

1. A compound of the following formula:

CHO

wherein R is a member of the group consisting of hydrogen and methyl; and R is selected from the group consisting of fluorine, chlorine and lower alkyl.

2. 16-formyl-6a-fluoro-A -androstadien-S-one.

. 16-forrnyl-6u-fluoro-l9-nor-A androstadien-3-one. 16-formyl-6a-chloro-A -androstadien-3-one. 16 formyl 6u-chloro-l9-nor-A -andr0stadien-3- one.

LII-bu) 16-formyl-6oc-methyl-A -androstadien-3-one. 7. 16 formyl 6a-rnethyl-19-nor-A -andrcstadien-3- one.

8. A compound of the following formula:

wherein R is selected from the group consisting of fluorine, chlorine and lower alkyl.

9. 16-formyl-6a-fluoro-A -androstatrien-3-one. 10. l6-formyl-6u-chloro-A -androstatrien-S-one. 11. 16-formyl-6a-methyl-A -androstatrien-3-one. 12. A compound of the following formula:

CHO

wherein R is selected from the group consisting of hydrogen and methyl; and R is a member of the group consisting of hydrogen and lower alkyl.

13. 16-formyl-A -androstadien-B-one.

l4. 16-formyl-19-nor-A -androstadien-3-one.

15. 16-formyl-2u-methyl-A -androstadien-3-one.

16. 16-formyl-2a-methyl-19-nor-A -androstadien.

17. A compound of the following formula:

g CH0 wherein R is selected from the group consisting of hydrogen and lower alkyl.

18. 16-formyl-A -androstatrien-B-one.

19. l6-forrnyl-2-methyl-A -androstatrien-3-one.

20. A process for the production of 16-formyl-A androsten derivatives which comprises treating the corresponding 17-keto compound with ethyl formate in the presence of an alkali metal hydride; hydrolyzing the resulting metal salt in a mild acid medium; methylating the resulting 16-hydroxymethylene-17-keto-androstane with a suitable methylating agent to form the respective 16- methoxymethylene-17-keto androstane derivative, reducing the keto group of this last mentioned compound with sodium borohydride to the corresponding 16-methoxymethylene-17,8-hydroxy-androstane derivative and finally treating this last named compound with a mild acid.

21. The process of claim 20 wherein the alkali metal hydride is sodium hydride, the mildacid medium is. aqueous tartaric acid solution, the suitable, methylating agent is diazomethane, and the mild acid' is 0.04%' acetonic hydrochloric acid solution.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 